Incidence and prevalence of musculoskeletal health conditions in survivors of childhood and adolescent cancers: A report from the Swiss childhood cancer survivor study

Abstract Purpose Childhood cancer and its treatment can cause damage to the musculoskeletal system. We aimed to determine the incidence and prevalence of musculoskeletal health conditions (MSHC) in survivors, and to investigate differences by cancer‐related characteristics. Methods We used data from the Childhood Cancer Registry and the Swiss Childhood Cancer Survivor Study, including survivors (≥5 years since diagnosis; diagnosed 1976–2015 at <20 years of age) aged ≥15 years at study. Cumulative incidence and prevalence of MSHCs (osteoporosis, limb length discrepancy, limited joint mobility, bone/joint pain, scoliosis, changes to chest/ribs and amputation) were calculated from self‐reported data. Results We included 2645 survivors (53% men; median age 24 years, range 15–59 years). Prevalence and cumulative incidence of any MSHC was 21% and 26%, respectively. Incidence rate for any MSHC was 15.6/1000 person‐years. Scoliosis (8%), bone/joint pain (7%) and limited joint mobility (7%) were the most prevalent MSHC. MSHC co‐occurred with other health conditions in 87% of survivors. We found increased rates of MSHC in women (RR = 1.4, 95%CI: 1.2–1.7), bone tumour survivors (RR = 6.0, 95%CI: 4.5–7.9), survivors older at diagnosis (11–15 years: RR = 1.8, 95%CI: 1.5–2.3), after a relapse (RR = 1.5, 95%CI: 1.3–1.9), treatment with surgery (RR = 1.2, 95%CI: 1.0–1.5), chemotherapy (RR = 1.4, 95%CI: 1.1–1.8) or stem cell transplantation (RR = 1.6, 95%CI: 1.0–2.5), and more recent year of diagnosis (2011–2015: RR = 4.3, 95%CI: 2.8–6.8). Conclusion MSHCs are prevalent in survivors, the risk is increasing in younger survivor cohorts, and MSHCs usually occur in multimorbid survivors. Strengthening of rehabilitation services and appropriate referrals are needed to mitigate the effects of the cancer and cancer treatment.


| INTRODUCTION
Damage to the musculoskeletal system by childhood cancer itself or its treatment can often not be prevented without jeopardising the patient's survival. 12][3][4][5] With improved survival rates, nowadays exceeding 80% in high-income countries, cancer-and treatment-related health conditions pose a considerable problem for childhood cancer survivors. 6n the general population, MSHCs are among the leading contributors to years lived with disability, 7 and, consequently, the leading contributor to the need for rehabilitation. 8Compared to the general population or siblings, MSHCs are more prevalent in CCS [9][10][11][12] : 10.4% of survivors in the in the Childhood Cancer Survivor Study experience MSHC compared to 1.4% of siblings (risk ratio 8.5 (95%CI: 6.5-11.2)). 12Data from the St. Jude Lifetime Cohort Study show that MSHCs are the third most common health problem in long-term CCS, with a cumulative incidence of 83.6% at age 50 years. 13Additionally, MSHCs are associated with low health-related quality of life in CCS, 9 and are among the late effects that have the strongest negative impact on physical functioning. 9,12MSHCs can also cause secondary complications, such as back pain, hip pain, fractures, muscular imbalances, gait abnormalities, or impaired mobility. 4,14,15Fortunately, many MSHCs are amenable to rehabilitation, and early intervention can help to prevent or ameliorate impaired physical functioning or disability. 168][19][20] Incidence of MSHCs is largest in the first years after diagnosis, but evidence suggests that MSHCs can also develop decades after diagnosis, 10 although there are differences by primary cancer diagnosis. 21All treatment modalities used for treating children and adolescents with cancer can cause MSHCs. 1,3SHCs seem to become more frequent with current treatment protocols, but this temporal trend has only been analysed in a subgroup of survivors of acute lymphoblastic leukaemia. 19There is also an indication for age-and sexspecific differences in MSHC after childhood cancer. 10,11st studies analysing MSHCs have merged them to a single outcome, disregarding distinct entities. 11,13,17,18nly few studies have presented results stratified for specific MSHCs. 10,12Other studies have determined incidence or prevalence of specific MSHCs, but in selected diagnostic groups only. 19,20,22,23We used data from a nationwide, population-based cohort study, the Swiss Childhood Cancer Survivor Study (SCCSS), (1) to determine the cumulative incidence, incidence rates, and prevalence of any and specific MSHCs (osteoporosis, arm-or leg-length discrepancy, limited joint mobility, persistent pain in bones or joints, scoliosis, amputation), and (2) to evaluate differences in incidence rates of any and the specific MSHCs by sex, age, type of cancer diagnosis, age at diagnosis, type of treatment and year of diagnosis.

| Survivor population
The Childhood Cancer Registry (ChCR) is a nationwide, population-based cancer registry for all Swiss residents diagnosed <20 years of age with leukaemia, lymphoma, central nervous system (CNS) tumours, malignant solid tumours, or Langerhans cell histiocytosis. 24The SCCSS is a nationwide, population-based, prospective cohort study including all children and adolescents registered in the ChCR, diagnosed with cancer since 1976 at an age of <20 years, who survived at least 5 years. 25For the current analysis, we included survivors aged ≥15 years at study, because information on MSHC was assessed differently in the questionnaire used in younger survivors.

| Setting
Survivors first received a letter with study information and the option to refuse participation from their former treatment clinic.Two weeks later, the SCCSS research team at the University of Bern sent survivors a paperbased questionnaire with a pre-paid return envelope.If they did not respond, they received a reminder letter with another questionnaire 4-6 weeks later, and then survivors were contacted by phone for a second reminder.The SCCSS questionnaire assessed information on health conditions, health service utilisation, health behaviours and socio-demographic characteristics.Data were collected from 2007 to 2022 and the overall response rate was 56%.Informed consent was obtained from all participating survivors.A detailed description of the SCCSS is provided elsewhere. 25thical approval of the SCCSS was granted by the Ethics Committee of the Canton of Bern (KEK-No.166/14 and 2021-01462).

| Musculoskeletal health conditions
The following MSHCs were assessed through self-report in the SCCSS questionnaire: osteoporosis, arm-or leg length discrepancy, limited joint mobility, persistent pain in bones or joints, scoliosis, changes to the chest and/or ribs.For each MSHC, participants were asked whether, at any time in their life, they had ever had this health condition (incidence: yes/no).If yes, they were asked to indicate since when they had this health condition (incidence year) and whether they were currently still experiencing it (prevalence: yes/no).Participants who answered 'no' or who left a question blank were included in the 'no' categories.If participants did not complete any question on health conditions, they were coded to have missing information.We additionally generated an overall variable (any MSHC) and coded 'yes' if participants experienced at least one of the MSHCs.
Information on musculoskeletal surgeries was coded from open answers to the question whether the participant had had any surgeries during or after their primary cancer treatment into amputation, rotationplasty, joint replacement or arthrodesis, limb lengthening/shortening, scoliosis surgery or spondylodesis, thorax surgery, surgery due to a fracture, or any other musculoskeletal surgery.We additionally generated an overall variable (any musculoskeletal surgery) and coded 'yes' if participants had had at least one of the above musculoskeletal surgeries.

| Explanatory variables
We obtained prospectively collected medical information from the ChCR: sex (male, female), cancer diagnosis (coded according to the International Classification of Childhood Cancer-3 26 ), surgery (yes/no), chemotherapy (yes/no), radiotherapy (yes/no), and stem cell transplantation (yes/no), year of diagnosis (1976-2015, 5-year increments), age at diagnosis (years), and relapse or second malignancy (yes/no).Age at study (years) was assessed in the SCCSS questionnaire.We calculated the sum of organ systems affected by health conditions as indicated by the participant (organ systems: neurological, musculoskeletal, heart/circulatory, vision, hearing, hormonal, respiratory, digestive, urinary, cancer-related fatigue and mental health).

| Data analysis
For all analyses, we used Stata version 17.0. 27All tests were two-sided and considered statistically significant if p < 0.05.Analyses are based on a completely anonymised dataset.We generated time since diagnosis (years), age at incidence (years), time since diagnosis at incidence (years), and categorical variables with a priori defined categories for: age at diagnosis (0-5 years, 6-10 years, 11-15 years and 16-20 years), time since diagnosis (5-50 years, 5-year increments), age at study (15-64 years, 10-year increments).
We used descriptive statistics to describe the prevalence, cumulative incidence, and incidence rate for any MSHC and each specific MSHC.We computed cumulative incidence and point prevalence for any MSHC and the specific MSHCs.We calculated the proportion of survivors for whom the condition is no longer prevalent.We computed incidence rates for any and the specific MSHCs by calculating the number of participants who answered incidence with 'yes' and divided by total observation time at risk.The starting point for time at risk was the age at diagnosis, the endpoint was the age at incidence, or the age at study for survivors who did not report a MSHC.We calculated incidence rates for any and specific MSHCs stratified by sex, age, cancer diagnosis, age at diagnosis, treatment, and year of diagnosis.We calculated rate ratios to compare different groups.
We calculated the missing values of the primary outcomes (Table S1).We present complete case analyses, as the performed sensitivity analyses showed that the results remained stable with different imputation scenarios.The complete case analysis provided the most conservative results (a detailed description and results of the sensitivity analyses are presented in Tables S4A-S6C).

| DISCUSSION
MSHC are prevalent in the survivors of childhood and adolescent cancers with increasing risk in younger cohorts The cumulative incidence of specific musculoskeletal health conditions stratified by diagnosis.The cumulative incidence (%) of musculoskeletal health conditions is presented; numbers can exceed 100% for the specific conditions, because survivors can experience more than one of the conditions simultaneously.Any musculoskeletal health condition and are commonly accompanied by other health conditions.Scoliosis, persistent pain in bones or joints and limited joint mobility are the most prevalent MSHC in this population.Risk for MSHCs is higher in female survivors, survivors of malignant bone tumours, survivors with a relapse, survivors who were aged 6-15 years at diagnosis, survivors treated with surgery, chemotherapy or stem cell therapy, and who were treated more recently.Prevalence of any MSHC in survivors in our study (21%) was similar to previous studies.The North American Childhood Cancer Survivor Study (CCSS) found that 10.4% of survivors reported prevalence of any MSHC, but they only assessed four types of MSHCs. 12A single-centre study from Switzerland found that 13.6% of CCS attending a follow-up care visit had a MSHC, 18 and a nationwide study from Poland found a prevalence of any MSHC of 19.2%. 17Regarding long-term cumulative incidence of any MSHC, Bhakta and colleagues found that at the of 50 years, 83.6% of survivors had experienced a MSHC, 13 which is higher than what we observed in our cohort.This difference may be attributed to the younger average age of our cohort.However, comparison of overall MSHCs across studies is difficult because of differing treatment protocols, MSHC assessed, age distributions of the cohorts, and the number of specific MSHC that were assessed-with more MSHC being assessed and with older age of the cohort, the higher the overall prevalence of MSHC.
For the specific MSHCs, the prevalence for osteoporosis in our study (2.4%) was similar to the 2.6% reported in the CCSS. 12We found a higher proportion of survivors reporting prevalent arm-or leg-length discrepancy (4.3%) than the CCSS (2.2%), 12 but these differences may be caused by the assessment of outcomes: in the CCSS, survivors were asked whether they had ever had a 'leg lengthening or shortening, or joint replacement', which may be more restrictive than the question in our survey ('arm-or leg-length discrepancy').
We are not aware of other studies that reported the prevalence of limited mobility of unspecified joints.However, a systematic review reported impaired ankle dorsiflexion in patients and survivors of childhood cancer. 28Further research is needed to clarify whether mobility limitations of other joints than the ankle joint are prevalent among CCS.
Various studies have investigated chronic pain in survivors, 29,30 but few with a specific focus on musculoskeletal pain: our study found that persistent pain in bones or joints was reported by 8% of survivors, which is lower than results from a study in Canada, which found that half of survivors who reported chronic pain (26.1%) located their pain in muscles or joints. 31r finding that 8% of survivors report scoliosis supports the lower range of results from a systematic review (scoliosis: 10%-80%, kyphosis: 2%-48%). 2 Prevalence of chest wall abnormalities (2%) was similar to that found in a recent systematic review (1.3%-2.2%). 32The prevalence of amputation or joint replacement in the CCSS was between 2.0%-2.7%, 11which is similar to our results (amputation: 2%, joint replacement: 1%).
Our study found an increased risk of osteoporosis and pain in bones and joints for female survivors.4][35] The IGHG guidelines for bone mineral density (BMD) surveillance found that osteoporosis risk is increased in male survivors. 15A cohort study of CCS from the Nordic countries (ALiCCS) found increased risk for osteoporosis in both male and female survivors, with a higher rate ratio in male survivors. 10One reason for the differences in findings could be that the ALiCCS study compared male survivors to male peers from the general population, and female survivors to female peers, whereas we directly compared male survivors to female survivors.The fact that osteoporosis is very rare in young men could then lead to higher rate ratios in men as compared to women.However, it is also possible that selfreport bias may play a role in our study, given the general health knowledge of osteoporosis occurring more often in women than men leading to more awareness for osteoporosis in women compared to men.This may have influenced self-report of both male and female survivors.
After stratifying for diagnosis, we found that age at diagnosis remained a significant predictor of MSHC, with higher incidence rates in survivors aged 6-15 years at diagnosis as compared to those diagnosed at 0-5 years.More specifically, age at diagnosis seems to be a relevant factor in the development of subsequent osteoporosis, limited joint mobility and persistent pain in bones or joints in CCS.Regarding increased risk for joint mobility deficits and pain in bones or joints, studies show that osteonecrosis risk is increased in children older at childhood cancer treatment (>10 years), 3 and is highest in leukaemia survivors. 10The leading symptom of osteonecrosis is pain in the affected joint, which may contribute to the increased risk for limited joint mobility and pain in bones and joints that we found in leukaemia survivors aged >10 years at diagnosis.However, as osteonecrosis is rare (prevalence of 2.5% in leukaemia survivors), 36 this can explain only a small fraction of the symptoms in our cohort.Other reasons for the impact of age at diagnosis on development of MSHC could be that the musculoskeletal system may be more vulnerable during the pubertal growth spurt, or that the bodies of T A B L E 3 Incidence rates (per 1000 person-years) and rate ratios of musculoskeletal health conditions in adolescent and adult 5-year survivors of childhood and adolescent cancer (unadjusted; total sample size: N = 2645).younger children may have a higher biological resilience to injuries of the musculoskeletal system.
Another study has also investigated temporal trends in the prevalence of MSHC: Mulrooney and colleagues found that low BMD and osteonecrosis were becoming more frequent in survivors of acute lymphoblastic leukaemia with current treatment protocols as compared to those treated according to older protocols. 19Our study provides evidence from an unselected cohort of CCS and found increasing incidence rates of MSHC in more recently diagnosed and treated survivors.This was most pronounced for osteoporosis, limited joint mobility, and persistent pain in bones or joints.Our results are in accordance with the results of Mulrooney et al., as increased frequency of osteonecrosis might partly explain the increased rates of bone and joint pain, as well as limited joint mobility.Also, with new treatment modalities, survival rates are increasing and life-threatening late effects are decreasing, 19,37 but this may in turn result in more survivors having poorer health. 37In accordance with this, a recent study of the CCSS showed increased rates of late major surgery of survivors diagnosed in the 1990s as compared to those diagnosed in the 1970s. 38nother possibility is that survivors are now better informed and more aware of potential late effects and may be more likely to report them, or that recall bias may play a role for those diagnosed less recently.Temporal trends in MSHC may therefore be partly real and partly artefactual and we would encourage longitudinal studies that investigate MSHCs from diagnosis to long-term follow-up care using objective measures.
Given that MSHC are prevalent in CCS, with increasing risk in cohorts diagnosed more recently, and usually occurring in multimorbid survivors, there is a need to strengthen rehabilitation services for survivors to address these challenges.MSHC are associated with impaired physical functioning, 12 and lower quality of life in survivors. 9The goal of rehabilitation is to improve physical functioning, 39 as well as prevention of secondary complications that can occur in persons with MSHC, for example, back pain, low-trauma fractures, or gait abnormalities. 14,15Several studies have highlighted the importance of rehabilitation in mitigating the impact of the cancer treatment and improving physical functioning of survivors. 16,40,414][45][46] Therefore, it is important to assess MSHCs in survivors during follow-up care, as follow-up care providers can initiate referral to rehabilitation services if indicated.
One strength of our study is its nationwide, populationbased design: Rueegg et al. showed that results of the SCCSS have low risk of nonresponse bias and are generalizable to the population of CCS in Switzerland. 47Other strengths are the good response rate of the SCCSS, the availability of objective diagnostic and treatment-related information from the ChCR, and the detailed assessment of specific MSHC.A limitation of this study are the selfreported primary outcomes, which introduce the potential for information bias.However, our results are similar to other studies in the field, which supports the validity of our results.Another limitation is the lack of a control group.However, results from the SCCSS have shown that prevalence of musculoskeletal and neurological health conditions (combined) in survivors was statistically significantly higher than in comparisons 9 -a finding that is consistent with the CCSS. 11n conclusion, MSHC are prevalent in survivors of childhood and adolescent cancers, risk is higher for more recent survivor cohorts, and MSHC usually occur in multimorbid survivors.Strengthening rehabilitation services, awareness of follow-up care providers, and appropriate referral to rehabilitation specialists are needed to mitigate the effects of the cancer and its treatment and improve survivors' physical functioning and quality of life.Note: Bold font indicates statistically significant difference as compared to the reference group at p < 0.05.
T A B L E 3 (Continued)

aFigure
Figure S1 displays years since diagnosis at incidence for the specific musculoskeletal health condition.b Number of survivors that indicated cumulative incidence 'yes' and prevalence 'no'.c Number of survivors that indicated cumulative incidence 'yes' and prevalence 'no' divided by number of survivors that indicated cumulative incidence 'yes'.d In survivors with a musculoskeletal health condition (N = 533 (100%)).e In survivors with a musculoskeletal surgery (N = 380 (100%)).
Characteristics of the study population (N = 2645).